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A Cell-Potent Bisubstrate Inhibitor to Probe NatD Acetyltransferase Activity
Yi-Hsun Ho1, Emma K Seipp1, Thitiwat Larndate1
1Borch Department of Medicinal Chemistry and Molecular Pharmacology, Purdue Institute for Drug Discovery, Purdue Institute for Cancer Research, Purdue University, West Lafayette, Indiana 47907, United States.
ACS Chemical Biology
|October 4, 2025
Summary
N-terminal acetyltransferase D (NatD) is crucial in lung cancer progression. A new cell-permeable inhibitor targeting NatD reduces cancer cell migration by modulating key protein expression, offering a potential therapeutic strategy.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- N-terminal acetyltransferase D (NatD) is an enzyme overexpressed in various cancers, including lung cancer.
- NatD's role in promoting cancer progression, particularly through epithelial-to-mesenchymal transition (EMT) in non-small cell lung cancer, highlights its potential as an epigenetic target.
- Existing NatD inhibitors lack cell permeability, hindering in-depth cellular studies.
Purpose of the Study:
- To develop a cell-permeable inhibitor for N-terminal acetyltransferase D (NatD) to investigate its function in cancer.
- To assess the efficacy of a novel cell-penetrating peptide (CPP)-conjugated NatD inhibitor in lung cancer cells.
Main Methods:
- Design and synthesis of cell-permeable bisubstrate analogs by conjugating cell-penetrating peptides (CPP) to a previously developed NatD inhibitor.
- In vitro enzymatic assays to determine the inhibitor's binding affinity (Ki).
- Cellular assays to evaluate the inhibitor's effect on histone H4 Nα-acetylation, cell migration, and the expression of EMT markers (E-cadherin, N-cadherin, vimentin).
Main Results:
- The CPP-conjugated NatD inhibitor exhibited a Ki value of 23 nM, indicating potent inhibition.
- The inhibitor effectively reduced cellular Nα-acetylation of histone H4 in lung cancer cells.
- Treatment with the inhibitor led to decreased lung cancer cell migration, associated with modulation of E-cadherin, N-cadherin, and vimentin expression.
Conclusions:
- The development of a cell-permeable CPP-conjugated NatD inhibitor provides a valuable chemical probe for studying NatD's biological roles in lung cancer.
- This novel inhibitor demonstrates potential for elucidating NatD's involvement in cancer progression and serves as a foundation for developing future NatD-targeted therapies.
